(a) Technical Field
The present disclosure relates to CML therapeutic agents with reduced drug-resistance and side-effect comprising 1,6-disubstituted indole compounds.
(b) Background Art
Chronic myelogenous leukemia (CML) is a type of hematologic malignancy caused by abnormally enlarged clones of hematopoietic stem cells with the Philadelphia chromosome. The Philadelphia chromosome results in the formation and continued activity of the Bcr-Abl fusion protein, which is the causative protein of CML. These abnormal Bcr-Abl proteins are expressed in more than 90% of patients with chronic myelogenous leukemia (CML) and about 40% of patients with acute lymphoblastic leukemia (ALL), and the sustained activity of Bcr-Abl further promotes leukemia. For this reason, Bcr-Abl tyrosine kinase has been regarded as a promising drug target for CML.
Imatinib as a therapeutic agent for chronic myelogenous leukemia has been commercialized and marketed as Gleevec, but a variety of point mutant species having Gleevec resistance have been reported recently. In particular, T315I, known as a gatekeeper mutant species, is not treated with Gleevec, nor with Nilotinib, Dasatinib, or Bosutinib, which are known as second-generation Bcr-Abl inhibitors. Although many studies have been conducted to overcome these gatekeeper mutant species, only Ponatinib has been reported to be the only drug approved for limited clinical use thus far.
Ponatinib has been reported to strongly inhibit wild-type Bcr-Abl and T315I-Bcr-Abl in vitro and in vivo, and has been exhibited to have excellent efficacy in phase 1 clinical trial (NCT00660920) and phase 2 clinical trial (NCT01207440) with patients with chronic myelogenous leukemia having T315I. However, it has been reported that Ponatinib may cause side-effects such as myelosuppression and pancreatitis due to low selectivity of kinase by simultaneously activating various kinases such as VEGFR2, PDGFR, KIT, FLT3, and FGFR (see Non-Patent Document 1). In addition, in the recent phase 3 clinical trial (NCT01650805), side-effects such as rapid cardiovascular disease caused by the strong VEGFR2 inhibitory effect of Ponatinib were observed and clinical trials and sales were discontinued (see Non-Patent Document 2). Therefore, it is urgently required to develop a therapeutic agent for CML which inhibits the activity of T315I-Bcr-Abl gatekeeper mutation, at the same time, has excellent selectivity for kinase, and in particular, does not have inhibitory activity for VEGFR2.
Meanwhile, the present inventors have synthesized 1,6-substituted novel indole compounds in Korean Patent Registration Publication No. 10-1116756 (Patent Document 1), and found that these compounds having inhibitory activity for B-Raf kinase and human melanoma cell lines (A375P, SK-MEL28), discloses that they are useful as a preventive and therapeutic agent for tumor diseases.